DOI: 10.1212/CPJ.0000000000000911 Neurology: Clinical ... · 7/23/2020 · Previously healthy...

Neurology: Clinical Practice Publish Ahead of PrintDOI: 10.1212/CPJ.0000000000000911

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Title: COVID-19 infection associated with encephalitis in an adolescent

Authors: Sejal M. Bhavsar, MD; Saranga Agarwal, MD; Rachel Lewis, MD; Avani Ganta, MBBS; Yelena S. Roshchina, MD; Katharine N. Clouser, MD; Aryeh Z. Baer, MD; Felicia Gliksman, MD; Julia A. Piwoz, MD

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Sejal M. Bhavsar, MD, Joseph M. Sanzari Children's Hospital at Hackensack University Medical Center and Hackensack Meridian School of Medicine, Department of Pediatrics, Hackensack, NJ, USA

Saranga Agarwal, MD, Joseph M. Sanzari Children's Hospital at Hackensack University Medical Center and Hackensack Meridian School of Medicine, Department of Pediatrics, Hackensack, NJ, USA Rachel Lewis, MD, Joseph M. Sanzari Children's Hospital at Hackensack University Medical Center and Hackensack Meridian School of Medicine, Department of Pediatrics, Hackensack, NJ, USA Avani Ganta, MBBS, Rutgers New Jersey Medical School, Department of Pediatrics, Newark, NJ, USA

Yelena S. Roshchina, MD, Joseph M. Sanzari Children's Hospital at Hackensack University Medical Center and Hackensack Meridian School of Medicine, Department of Pediatrics, Hackensack, NJ, USA Katharine N. Clouser, MD, Joseph M. Sanzari Children's Hospital at Hackensack University Medical Center and Hackensack Meridian School of Medicine, Department of Pediatrics, Hackensack, NJ, USA Aryeh Z. Baer, MD, Joseph M. Sanzari Children's Hospital at Hackensack University Medical Center and Hackensack Meridian School of Medicine, Department of Pediatrics, Hackensack, NJ, USA Felicia Gliksman, MD, Joseph M. Sanzari Children's Hospital at Hackensack University Medical Center and Hackensack Meridian School of Medicine, Department of Pediatrics, Hackensack, NJ, USA Julia A. Piwoz, MD, Joseph M. Sanzari Children's Hospital at Hackensack University Medical Center and Hackensack Meridian School of Medicine, Department of Pediatrics, Hackensack, NJ, USA

Search terms: COVID-19, Pediatric encephalitis

Submission type: Full case Title character count: 57

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Number of tables: 3 Number of figures: 0

Word count of abstract: 79 Word count of paper: 1,099

Corresponding Author: Sejal Makvana Bhavsar, MD, [email protected]

Saranga Agarwal [email protected]

Rachel Lewis [email protected]

Avani Ganta [email protected]

Yelena Roshchina [email protected]

Katharine Clouser [email protected]

Aryeh Baer [email protected]

Felicia Gliksman [email protected]

Julia Piwoz [email protected]

Financial disclosures: None

Study funding: None

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Abstract

Although adults with coronavirus disease 2019 (COVID-19) who require admission to the

hospital have often required critical care, infants and children with COVID-19 have generally

demonstrated milder disease severity, fewer complications, and overall a much lower case

fatality rate (1-2). Neurologic manifestations have been reported with COVID-19 in adult

patients including acute cerebrovascular disease, ischemic and hemorrhagic strokes, skeletal

muscle injury and rare cases of encephalopathy (3-5). We report here an adolescent patient with

acute encephalitis associated with COVID-19.

Case Presentation

A 16 year old previously healthy male presented to the Emergency Department (ED) at The

Joseph M. Sanzari Children’s Hospital at Hackensack University Medical Center with fever up

to 101oF for nine days followed by generalized weakness and somnolence for two days. He had

pharyngitis and intermittent headaches, which prompted evaluation at a local ED four days prior

to admission. There, rapid tests for influenza and streptococcal pharyngitis were negative. He

was prescribed amoxicillin, and, given the ongoing COVID-19 pandemic, he was instructed to

self-isolate at home. Two days after, he developed emesis, severe malaise, progressive

somnolence with confusion, and incoherent speech. He was not able to ambulate without

assistance, which prompted re-evaluation in our ED.

In the ED, he was afebrile, normotensive, and had an arterial oxygen saturation of 98% on room

air. Upon neurological examination, he was difficult to arouse, confused, speaking incoherently

and following commands inconsistently. No papilledema was noted and his cranial nerve exam

was normal. Motor exam was significant for mild to moderate generalized weakness without any

focal findings. His DTRs were normal with negative Babinski bilaterally. He was noted to have

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frequent episodes of eye rolling, lip smacking and insuppressible left facial and hand twitching

for few seconds, which were treated as clinical seizures with 2mg of Lorazepam. The movements

recurred soon after, which resolved after receiving 1gram of levetiracetam. He had a normal

cardiopulmonary examination. Abdominal examination was notable for suprapubic tenderness.

There was no rash. Computed tomography (CT) of his head without contrast was normal. A CT

scan of his abdomen and pelvis with IV contrast showed bilateral dependent patchy lower lung

ground-glass opacities. Chest radiograph had low lung volumes with possible left lower lobe

infiltrate. Complete blood count (CBC), C-reactive protein (CRP), Erythrocyte sedimentation

rate (ESR) obtained secondary to suspicion for infection, were normal. A total CK value was

obtained due to his complaint of weakness, which was found to be elevated to 1200 U/L. He had

hyponatremia (124 mmol/L) with a serum osmolality of 263 mOsm/kg. A urine osmolality of

900 mOsm/kg was suggestive of diagnosis of Syndrome of Inappropriate Anti-Diuretic Hormone

(SIADH) (Table 1). Urine drug screen was negative. Respiratory pathogen panel (RPP) by PCR

was negative for common respiratory viruses and atypical bacterial pathogens (Table 2).

Due to concern for meningoencephalitis, a lumbar puncture was performed. Cerebrospinal fluid

(CSF) was clear and had 122 white blood cells/µL with mononuclear cells predominance. There

were 239 red blood cells/mcL, protein was 173 mg/dL and glucose was 35 mg/dL (serum

glucose 109 mg/dL). The Gram stain of his CSF showed no cells or organisms. A

meningoencephalitis PCR panel (Biofire ME Film Array) was negative for common viral and

bacterial pathogens (Table 3).

The patient was started on vancomycin and ceftriaxone and was admitted to the pediatric

intensive care unit (PICU) for neurocritical monitoring for acute encephalitis and correction of

hyponatremia. After admission, he became hypothermic with temperatures as low as 91.1F

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rectally, which slowly improved to normal with external warming measures. He had bradycardia,

with rates in the 50s, but his perfusion remained normal and he was normotensive. He continued

to be lethargic, oriented to name only, and inconsistently followed commands and answered

questions. Cranial nerve examination was normal and he displayed generalized weakness with no

focal motor or sensory deficits. Supplemental oxygen via nasal cannula was required briefly in

concurrence with alteration of mental status, hypoventilation, and difficulty handling oral

secretions. Hyponatremia was initially treated with fluid restriction and hypertonic saline. He

was placed on video electroencephalogram (EEG), which was consistent with encephalopathy,

showing slow background without epileptiform discharges or seizures. Further investigation for

etiology of encephalitis was performed on serum including negative testing for auto-immune

encephalopathy antibody panel. Syphilis and human immunodeficiency virus antibodies were

non-reactive. Interferon gamma release assay, Lyme ELISA and serum Epstein Barr virus and

CMV PCRs were negative. SARS-CoV-2 testing by in house RT-PCR from his nasopharynx

obtained in the ED resulted as positive. His CSF was experimentally tested for SARS-CoV-2,

which was not detected. Antibiotics were discontinued once blood and CSF cultures were

negative for 48 hours. Compassionate use of remdesivir for a 10 day course was initiated. The

patient’s neurologic symptoms started to improve by hospital day four and he was transferred to

a lower level of care. During his stay, he continued to have moderate hyponatremia with serum

sodium level between 129-133 mmol/L which improved with oral sodium chloride supplements.

His mental status remained altered, with inconsistent awareness of time and place, despite

normalization of his labs. One week into admission, he developed pain to palpation in his right

gastrocnemius. A venous doppler confirmed an infrapopliteal deep venous thrombosis and he

was started on Lovenox which prolonged his hospital stay. He was discharged home on day 15

with improved mental status and condition, with outpatient therapies arranged.

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Discussion

Previously healthy children have rarely been reported to have severe manifestations with

COVID-19 (1-2). Our report illustrates an adolescent patient with severe infection with

neurologic involvement. Neurologic manifestations have been reported in adult patients with

COVID-19 including rare cases of encephalopathy (3-5). However, true encephalitis with

evidence of central nervous system inflammation in CSF analysis has not yet been reported.

There are reports of human coronaviruses associated with neurologic manifestations (6). There

has been a single report of human coronavirus associated with encephalitis in an 11-month-old

boy with severe combined immunodeficiency which was diagnosed by a post-mortem brain

biopsy (7). Acute disseminated encephalomyelitis (ADEM) has also been associated with human

coronaviruses, including in a 15 year old male who presented with irritability, focal neurologic

findings (right hand weakness, left hand dysmetria, bilateral leg numbness and difficulty

walking) and had brain and spine MRI showing multifocal lesions (8). Brain magnetic

resonance imaging (MRI) can be useful in differentiating these conditions. Our report is limited

in that a brain MRI was not performed in order to limit SARS-CoV-2 exposure within the

hospital. In light of his normal CT findings, non-focal neurological exam and improving

neurological exam, brain MRI was deferred. If he did decompensate, then brain MRI would have

been performed. Although our patient did not present typically with respiratory symptoms, his

chest imaging was consistent with COVID-19 with the findings of bilateral ground glass

opacities. He also later developed deep vein thrombosis which coincides with reports of

increased incidence of thrombotic complications in critically ill ICU patients with COVID-19

(9).

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As our patient illustrates, encephalitis may be associated with COVID-19. Patients presenting

with symptoms compatible with COVID-19 and encephalitis should be tested for SARS-CoV-2

in addition to the usual pathogens associated with neurological infections.

Appendix - Authors:

Name Location Role Contribution

Sejal M. Bhavsar, MD Joseph M. Sanzari Children's Hospital at Hackensack University Medical Center

Author Drafted original manuscript and revision of manuscript

Saranga Agarwal, MD Joseph M. Sanzari Children's Hospital at Hackensack University Medical Center

Author Drafted original manuscript and revision of manuscript

Rachel Lewis, MD Joseph M. Sanzari Children's Hospital at Hackensack University Medical Center

Author Reviewed and revised the manuscript

Avani Ganta, MBBS Rutger's New Jersey Medical School


Yelena Roshchina, MD

Joseph M. Sanzari Children's Hospital at Hackensack University Medical Center


Katharine Clouser, MD

Joseph M. Sanzari Children's Hospital at Hackensack University Medical Center


Aryeh Baer MD Joseph M. Sanzari Children's Hospital at Hackensack University Medical Center

Author Drafted original manuscript, reviewed manuscript

Felicia Gliksman, MD Joseph M. Sanzari Children's Hospital at Hackensack University Medical Center


Julia Piwoz, MD Joseph M. Sanzari Children's Hospital at Hackensack University Medical Center


References: 1. Dong Y, Mo X, Hu Y, et al. Epidemiological characteristics of 2143 pediatric patients with 2019 coronavirus disease in China. Pediatrics. 2020; doi: 10.1542/peds.2020-0702

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2. Severe Outcomes Among Patients with Coronavirus Disease 2019 (COVID-19) — United States, February 12–March 16, 2020: MMWR: Early Release / March 18, 2020 / 69

3. Mao L, Jin H, Wang M, et al. Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease 2019 in Wuhan, China. JAMA Neurol. Published online April 10, 2020. doi:10.1001/jamaneurol.2020.1127

4. Helms J, Kremer S, Merdji H, et al. Neurologic Features in Severe SARS-CoV2 Infection. NEJM. April 15, 2020. doi:10.1056/NEJMc2008597

5. Filatov A, Sharma P, Hindi F, et al. (March 21, 2020) Neurological Complications of Coronavirus Disease (COVID-19): Encephalopathy. Cureus 12(3): e7352. doi:10.7759/cureus.7352

6. Desforges M, Le Coupanec A, Dubeau P, et al. Human Coronaviruses and Other Respiratory Viruses: Underestimated Opportunistic Pathogens of the Central Nervous System? Viruses. 2019 Dec 20;12(1). pii: E14. doi: 10.3390/v1201001

7. Morfopoulou S., Brown J.R., Davies E.G., Anderson G., Virasami A., Qasim W., Chong W.K., Hubank M., Plagnol V., Desforges M., et al. Human Coronavirus OC43 Associated with Fatal Encephalitis. N. Engl. J. Med. 2016;375:497–498. doi: 10.1056/NEJMc1509458

8. Yeh E.A., Collins A., Cohen M.E., Duffner P.K., Faden H. Detection of coronavirus in the central nervous system of a child with acute disseminated encephalomyelitis. Pediatrics. 2004;113:e73–e76.

9. Klok FA, Kruip MJHA, van der Meer NJM, et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res. April 10, 2020. doi:10.1016/j.thromres.2020.04.013.

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Table 1: Laboratory Results

WBC 7,500 cells/mcL Hemoglobin 13.8 gm/dL Platelets 233,000 cells/mcL Neutrophil % 71 % Lymphocyte % 15 % Monocyte % 11 % Eosinophil % 3 % Sodium 124 mmol/L Potassium 4 mmol/L Chloride 94 mmol/L CO2 21 mmol/L BUN 17 mg/dL Creatinine 0.7 mg/dL Glucose 109 mg/dL Calcium 9 mg/dL Total protein 7.5 mg/dL Albumin 4.3 mg/dL Total bilirubin 0.7 mg/dL AST 29 U/L ALT 26 U/L CPK 1210 U/L TSH 2.83 uIU/mL CRP 0.1 mg/dL ESR 9 mm/hr Procalcitonin 0.05 ng/mL Serum Osm 263 mOsm/kg Urine sodium 22 mmol/L Urine Osm 900 mOsm/kg

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Table 2: Respiratory Pathogen Panel

Respiratory Pathogen Panel Adenovirus Not detected Human metapneumovirus Not detected Human coronaviruses Not detected Respiratory syncytial virus Not detected Rhinovirus/enterovirus Not detected Influenza A or B Not detected Parainfluenza virus types 1-4 Not detected Bordetella pertussis Not detected Mycoplasma pneumoniae Not detected Chlamydophilia pneumoniae Not detected

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Table 3: Cerebrospinal Fluid Analysis

CSF WBC 122 cells/mcL

CSF PMN% 2 % CSF lymph% 74 % CSF reactive lymph % 7 % CSF monocyte % 11% CSF RBC 239

cells/mcL CSF protein 173 mg/dL CSF glucose 35 mg/dL

CSF Meningoencephalitis PCR panel: Herpes Simplex virus 1 and 2 Not detected Varicella zoster virus Not detected Enterovirus Not detected Human herpesvirus 6 Not detected Cytomegalovirus Not detected Human parechovirus Not detected Streptococcus pneumoniae Not detected Neisseria meningitidis Not detected Haemophilus influenzae Not detected Streptococcus agalactie Not detected Listeria monocytogenes Not detected Escherichia coli K1 Not detected

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DOI 10.1212/CPJ.0000000000000911 published online July 28, 2020Neurol Clin Pract

Sejal M. Bhavsar, Saranga Agarwal, Rachel Lewis, et al. COVID-19 infection associated with encephalitis in an adolescent

This information is current as of July 28, 2020

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